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The layered learning model (LLM) is a well-established teaching approach designed for attending preceptors to train post-graduate learners and to precept students. The adaptation of a LLM to a virtual exchange program has not been previously described. The purpose of this study was to evaluate the effectiveness of the longitudinal virtual international exchange program in applying principles of the LLM to multiple levels of learners and instructors at West Virginia University (WVU) School of Pharmacy and Kitasato University (KU) School of Pharmacy.The online survey piloted the impact of applying the LLM to virtual international exchange sessions on improving participant knowledge in pharmacy practice, pharmacy education, cultural practices, and cultural awareness. The survey questions assessed the program's structure and effectiveness in achieving learning outcomes related to pharmacy residency topics and cultural competency using a five-point Likert scale.Median scores of the effectiveness of the virtual international exchange program structure were high (≥ 4.0). Two questions evaluating the use of the LLM had median scores of 4.0. All nine residency-related questions were rated ≥3.0. The median scores for three questions evaluating small group discussions and the use of the LLM were rated significantly higher by WVU participants than KU participants. There were no significant differences in program structure and learning outcome ratings between participant groups (student vs. resident/fellow vs. preceptor/faculty).Application of the LLM to the virtual international exchange program was positively received by participants, particularly by United States participants.

BackgroundCurrent diagnosis and classification of thyroid nodules are susceptible to subjective factors. Despite widespread use of ultrasonography (USG) and fine needle aspiration cytology (FNAC) to assess thyroid nodules, the interpretation of results is nuanced and requires specialist endocrine surgery input. Using readily available pre-operative data, the aims of this study were to develop artificial intelligence (AI) models to classify nodules into likely benign or malignant and to compare the diagnostic performance of the models.MethodsPatients undergoing surgery for thyroid nodules between 2010 and 2020 were recruited from our institution’s database into training and testing groups. Demographics, serum TSH level, cytology, ultrasonography features and histopathology data were extracted. The training group USG images were re-reviewed by a study radiologist experienced in thyroid USG, who reported the relevant features and supplemented with data extracted from existing reports to reduce sampling bias. Testing group USG features were extracted solely from existing reports to reflect real-life practice of a non-thyroid specialist. We developed four AI models based on classification algorithms (k-Nearest Neighbour, Support Vector Machine, Decision Tree, Naïve Bayes) and evaluated their diagnostic performance of thyroid malignancy.ResultsIn the training group (n = 857), 75% were female and 27% of cases were malignant. The testing group (n = 198) consisted of 77% females and 17% malignant cases. Mean age was 54.7 ± 16.2 years for the training group and 50.1 ± 17.4 years for the testing group. Following validation with the testing group, support vector machine classifier was found to perform best in predicting final histopathology with an accuracy of 89%, sensitivity 89%, specificity 83%, F-score 94% and AUROC 0.86.ConclusionWe have developed a first of its kind, pilot AI model that can accurately predict malignancy in thyroid nodules using USG features, FNAC, demographics and serum TSH. There is potential for a model like this to be used as a decision support tool in under-resourced areas as well as by non-thyroid specialists.

Background: The authors aimed to assess outcomes with a pharmacogenetic (PGx)-informed, pharmacist-guided, personalized consult service for warfarin dosing. Methods: This retrospective cohort study included patients admitted with thromboembolic events. Eligible subjects received either PGx-informed (n = 389) or historical non-PGx pharmacist-guided warfarin dosing (Hx; n = 308) before hospital discharge. The composite of admission with bleeding or thromboembolic events over 90 days after the discharge was compared between the PGx and Hx groups. Results: The rate ratio (95% CI) of the composite of bleeding or thromboembolic admissions for PGx versus Hx was 0.32 (0.12–0.82). The estimated hazard ratio was 0.43 (0.16–1.12). Conclusion: A PGx-informed warfarin dosing service was associated with decreased bleeding and thromboembolic encounters.

Alveolar bone grafting is an important component of cleft lip and palate treatment, with iliac crest as the most common donor site. Although studies have attempted to quantify alveolar bone graft resorption, few have directly compared the outcomes of graft techniques. This study compared the long-term success rates of corticocancellous block to trephine cancellous-only alveolar bone grafting from the iliac crest.A retrospective review of all cleft lip and palate patients undergoing alveolar bone grafting over 14 years was performed. Power analysis was performed to determine sample size. Data including patient demographics, surgical technique, need for repeated grafting, complications, length of hospitalization, and follow-up were collected. Statistical analyses of outcomes were performed based on initial graft technique.A total of 106 initial operations met criteria, with 73 using trephine technique, 30 using corticocancellous block, and three undergoing open cancellous harvest. The overall regraft rate was 40 percent, with an average follow-up of 43.5 months. Patients with corticocancellous block grafting had significantly lower rates of repeated grafting compared to trephine technique (16.7 percent versus 47.9 percent; p0.001). There was no significant difference in complication rates or length of admission between treatment groups.The use of corticocancellous block alveolar bone grafting demonstrated significantly higher success rates when compared to cancellous-only trephine techniques, with no difference in complication rates. Although this must be weighed against the minor disadvantages of open iliac harvest, surgeons should consider incorporating en bloc corticocancellous bone to optimize outcomes in alveolar bone grafting.Therapeutic, III.

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease, with a clear genetic component. While most SLE patients carry rare gene variants in lupus risk genes, little is known about their contribution to disease pathogenesis. Amongst them,SH2B3- a negative regulator of cytokine and growth factor receptor signaling – harbors rare coding variants in over 5% of SLE patients. Here we show that unlike the variant found exclusively in healthy controls, mostSH2B3rare variants found in lupus patients are predominantly hypomorphic alleles. Generation of two mouse lines carrying variants orthologous to those found in patients revealed SH2B3 is important to limit the numbers of immature and transitional B cells. Furthermore, hypomorphic SH2B3 was shown to impair negative selection of immature/transitional self-reactive B cells and accelerate autoimmunity in sensitized mice, at least in part due to increased IL-4R signaling and BAFF-R expression. This work identifies a previously unappreciated role forSH2B3in human B cell tolerance and lupus risk.SummaryZhanget al. reveal a role for hypomorphic SH2B3 in lupus risk. The study shows rare and damaging variants identified in lupus patients enable breach of B cell immune tolerance checkpoints and suggests involvement for dysregulated IL-4R signaling and BAFF-R expression.

The increase in healthcare coverage for transgender populations has made facial feminization surgeries (FFS) more accessible. Majority of patients interested in surgery regularly check online medical information to help understand surgical procedures, risks, and recovery. National health organizations recommend that patient information material should be written at a sixth-grade-reading level, but online material often surpasses patient health literacy. This study evaluates the readability of online FFS resources. An Internet search of the top 100 Web sites was conducted using the keywords "facial feminization surgery." Web sites were analyzed for relevant patient information articles on FFS and categorized into health care and nonhealth care groups. Readability examinations were performed for written text using the Automated Readability Index, Coleman-Liau Index, Flesch-Kincaid Grade Level, Gunning Fog Index, and Simple Measure of Gobbledygook Index. Statistical analysis was performed using 2-tailed z tests, with statistical significance set at P≤0.05. A total of 100 articles from 100 Web sites were examined. The average readability for all online FFS resources was at a 12th-grade-writing level. Articles from health care organizations were at a 13th-grade-reading level and nonhealth care organization articles were at a 12th-grade-reading level (P0.01). Online patient information for FFS is more complex than nationally recommended writing levels, which may interfere with patient decision making and outcomes. Patient resources for FFS should be written at a lower reading level to promote patient education, satisfaction, and compliance.

Medullary thyroid cancer (MTC) is rare, with poorer outcomes than differentiated thyroid cancer. We aimed to identify areas for improvement in the pre-operative evaluation of patients with possible MTC in a high-volume endocrine surgery unit in accordance with current practice guidelines. We hypothesised that the selective use of serum calcitonin (sCT) as a biomarker for possible MTC could guide the extent of initial surgical management.We recruited MTC patients between 2000 and 2020 from the Monash University Endocrine Surgery Unit database. Demographics, tumour characteristics, pre-operative evaluation, operative management, and outcomes were analysed.Of 1454 thyroid cancer patients, 43 (3%) had MTC. Pre-operatively, 36 (84%) patients with MTC confirmed on cytology (28, 65%), elevated sCT (6, 14%) or RET mutation (2, 4%). Of these 36 patients, 31 (86%) had optimal extent of thyroidectomy and lymph node dissection (LND). Five (14%) had less than total thyroidectomy due to nerve injury. Thirty-four patients had compartmental LND. In the 12 (27%) patients with indeterminate or non-diagnostic cytology, 5 had elevated sCT and were managed as above. None of the remaining seven had LND, thus potentially suboptimal surgery.Our findings reflect the rarity of MTC, and the challenges of pre-operative diagnosis. The addition of sCT may improve surgical planning in patients with indeterminate cytology.

Obesity imposes well-established deficits to endothelial function. We recently showed that obesity-induced endothelial dysfunction was mediated by disruption of the glycocalyx and a loss of Kir channel flow sensitivity. However, obesity-induced endothelial dysfunction is not observed in all vascular beds: visceral adipose arteries (VAAs), but not subcutaneous adipose arteries (SAAs), exhibit endothelial dysfunction. To determine whether differences in SAA versus VAA endothelial function observed in obesity are attributed to differential impairment of Kir channels and alterations to the glycocalyx, mice were fed a normal rodent diet, or a high-fat Western diet to induce obesity. Flow-induced vasodilation (FIV) was measured ex vivo. Functional downregulation of endothelial Kir2.1 was accomplished by transducing adipose arteries from mice and obese humans with adenovirus containing a dominant-negative Kir2.1 construct. Kir function was tested in freshly isolated endothelial cells seeded in a flow chamber for electrophysiological recordings under fluid shear. Atomic force microscopy was used to assess biophysical properties of the glycocalyx. Endothelial dysfunction was observed in VAAs of obese mice and humans. Downregulating Kir2.1 blunted FIV in SAAs, but had no effect on VAAs, from obese mice and humans. Obesity abolished Kir shear sensitivity in VAA endothelial cells and significantly altered the VAA glycocalyx. In contrast, Kir shear sensitivity was observed in SAA endothelial cells from obese mice and effects on SAA glycocalyx were less pronounced. We reveal distinct differences in Kir function and alterations to the glycocalyx that we propose contribute to the dichotomy in SAA versus VAA endothelial function with obesity. NEW & NOTEWORTHY We identified a role for endothelial Kir2.1 in the differences observed in VAA versus SAA endothelial function with obesity. The endothelial glycocalyx, a regulator of Kir activation by shear, is unequally perturbed in VAAs as compared with SAAs, which we propose results in a near complete loss of VAA endothelial Kir shear sensitivity and endothelial dysfunction. We propose that these differences underly the preserved endothelial function of SAA in obese mice and humans.

Facial feminization surgery (FFS) refers to a set of procedures aimed at altering the features of a masculine face to achieve a more feminine appearance. In the second part of this twopart series, assessment and operations involving the midface, mandible, and chin, as well as soft tissue modification of the nasolabial complex and chondrolaryngoplasty, are discussed. Finally, we provide a review of the literature on patient-reported outcomes in this population following FFS and suggest a path forward to optimize care for FFS patients.

Background Chronic active antibody-mediated rejection (AMR) is a major cause of graft loss with no approved drugs for its treatment. Currently, off-label regimens are used, reflecting the high unmet need for effective therapies based on well-controlled trials. Clazakizumab is a high-affinity, humanized monoclonal antibody that binds interleukin-6 and decreases donor-specific antibody (DSA) production and inflammation. Phase 2 pilot studies of clazakizumab in kidney transplant recipients with chronic active AMR suggest modulation of DSA, stabilization of glomerular filtration rate (GFR), and a manageable safety profile. We report the design of the Phase 3 IMAGINE study (NCT03744910) to evaluate the safety and efficacy of clazakizumab for the treatment of chronic active AMR. Methods IMAGINE is a multicenter, double-blind trial of approximately 350 kidney transplant recipients with chronic active AMR (Banff chronic glomerulopathy [cg] >0 with concurrent positive human leukocyte antigen DSA) randomized 1:1 to receive clazakizumab or placebo (12.5 mg subcutaneous once every 4 weeks). The event-driven trial design will follow patients until 221 occurrences of all-cause graft loss are observed, defined as return to dialysis, graft nephrectomy, re-transplantation, estimated GFR (eGFR) 2, or death from any cause. A surrogate for graft loss (eGFR slope) will be assessed at 1 year based on prior modeling validation. Secondary endpoints will include measures of pharmacokinetics/pharmacodynamics. Recruitment is ongoing across North America, Europe, Asia, and Australia. Discussion IMAGINE represents the first Phase 3 clinical trial investigating the safety and efficacy of clazakizumab in kidney transplant recipients with chronic active AMR, and the largest placebo-controlled trial in this patient population. This trial includes prognostic biomarker enrichment and uniquely utilizes the eGFR slope at 1 year as a surrogate endpoint for graft loss, which may accelerate the approval of a novel therapy for patients at risk of graft loss. The findings of this study will be fundamental in helping to address the unmet need for novel therapies for chronic active AMR. Trial registration ClinicalTrials.govNCT03744910. Registered on November 19, 2018.

ObjectiveTo evaluate the cost-effectiveness of a personalised medicine strategy for Crohn’s disease in the UK, using early targeted top-down therapy compared to standard of care.Materials & MethodsA decision tree leading into a Markov state-transition model was constructed, allowing comparison of two treatment approaches: 1) standard of care therapy following established UK clinical guidelines (‘step-up’ treatment) and 2) a personalised medicine strategy in which patients identified as high-risk of subsequent relapse using a prognostic biomarker receive ‘top-down’ anti-TNF treatment at diagnosis. The model facilitated comparison of both costs and Quality Adjusted Life Years (QALYs) in a hypothetical cohort of newly diagnosed Crohn’s disease patients with sensitivity analyses undertaken to model the impact of key assumptions.ResultsEarly personalised treatment with anti-TNF based combination therapy resulted in an incremental cost-effectiveness ratio (ICER) of £2,176 per quality-adjusted life year (QALY), with £717 incremental costs and 0.330 incremental QALYs, substantially below the NICE cost-effectiveness threshold of between £20,000 and £30,000 per QALY. Additional costs relating to earlier biologic use were offset by incremental QALYS and reductions in costs driven by fewer disease flares and hospitalisations. Sensitivity analysis across a wide range of parameter assumptions did not impact on the model’s conclusion.ConclusionA personalised medicine strategy using anti-TNF therapy at diagnosis in Crohn’s disease to patients at high risk of subsequent relapse is highly likely to be a cost-effective use of resources in the UK National Health Service.KEY SUMMARYEstablished KnowledgeCurrently there are no validated prognostic test that can stratify IBD patients based on long term outcomes at the point of diagnosis used routinely in the UKIt therefore remains unclear which patients with Crohn’s disease should be treated with early anti-TNF based therapy as part of a ‘top-down’ regimen.As a consequence, the majority of IBD patients in the UK are currently treated with an accelerated step-up approachSignificant new findingsWe show here that the use of biomarkers at diagnosis to guide personalised use of such treatment is a cost-effective approach for treatment of Crohn’s disease.Use of a prognostic test to deliver personalised medicine for Crohn’s disease results in positive QALY of 0.330The approach is cost effective with an incremental cost of £717 and an ICER of 2,176The model’s conclusions were unaffected by a wide range of sensitivity analyses

Warfarin dosing varies due to individual genetic and clinical factors. The utility of genotype‐guided warfarin dosing to improve stable warfarin dose is not extensively studied in non-European popu...

Informed consent for surgery is a medical and legal requirement, but completing these does not necessarily translate to high patient satisfaction. This patient-reported experience study aimed to examine the surgical consent process, comparing the patients' experience in elective and emergency settings.Over a 6-mo period, postoperative patients at The Alfred Hospital Breast and Endocrine Surgical Unit were invited to participate in a survey on the surgical consent process - including perceived priorities, information provided and overall experience. Standard statistical techniques were used, with a significant P-value of0.05.A total of 412 patients were invited, with 130 (32%) responses. More patients underwent elective surgery (N= 90, 69%) than emergency surgery (N = 40, 31%). Emergency patients were more likely to sign the consent form regardless of its contents (93% versus 39%, P0.001) and more likely to be influenced by external pressures (63% versus 1%, P0.001). Elective patients were more likely to want to discuss their surgery with a senior surgeon (74% versus 23%, P0.001) and more likely to seek advice from external sources (83% versus 10%, P0.001). Both groups highly valued the opportunity to ask questions (67% versus 63%, P = 0.65).This study shows patients have a range of different priorities in preparation for surgery. Therefore, each consent process should be patient-specific, and focus on providing the patient with quality resources that inform decision-making.

Endothelial stiffness is emerging as a major determinant in endothelial function. Here, we analyzed the role of caveolin-1 (Cav-1) in determining the stiffness of endothelial cells (EC) exposed to oxidized low density lipoprotein (oxLDL) under static and hemodynamic conditions in vitro and of aortic endothelium in vivo in mouse models of dyslipidemia and ageing. Elastic moduli of cultured ECs and of the endothelial monolayer of freshly isolated mouse aortas were measured using atomic force microscopy (AFM). We found that a loss of Cav-1 abrogates the uptake of oxLDL and oxLDL-induced endothelial stiffening, as well as endothelial stiffening induced by disturbed flow (DF), which was also oxLDL dependent. Mechanistically, Cav-1 is required for the expression of CD36 (cluster of differentiation 36) scavenger receptor. Genetic deletion of Cav-1 abrogated endothelial stiffening observed in the DF region of the aortic arch, and induced by a high fat diet (4–6 weeks) and significantly blunted endothelial stiffening that develops with advanced age. This effect was independent of stiffening of the sub-endothelium layer. Additionally, Cav-1 expression significantly increased with age. No differences in elastic modulus were observed between the sexes in advanced aged wild type and Cav-1 knockout mice. Taken together, this study demonstrates that Cav-1 plays a critical role in endothelial stiffening induced by oxLDL in vitro and by dyslipidemia, disturbed flow and ageing in vivo.

63 p.-6 fig., Dr. Serge N. Timasheff, our mentor and friend, passed away in 2019. This article is a collection of tributes from his postdoctoral fellows, friends, and daughter, who all have been associated with or influenced by him or his research. Dr. Timasheff is a pioneer of research on thermodynamic linkage between ligand interaction and macromolecular reaction. We all learned a great deal from Dr. Timasheff, not only about science but also about life.

Black patients suffer worse outcomes after percutaneous coronary intervention (PCI) than White patients. Inequities in antiplatelet prescribing may contribute to this health disparity. We compared P2Y

The warfarin dose requirement and therapeutic response of a 42-year-old African–American male with genotype CYP2C9 *11/*11, VKORC1 -1639GG and CYP4F2 433Val/Val anticoagulated for ischemic stroke is described herein. Warfarin was dosed according to the institution’s personalized medicine program recommendations of a 10 mg mini-load dose, followed by dose decreases to 4–6 mg/day through discharge. Stable international normalized ratio was achieved after eight doses, with good overall long-term maintenance of therapeutic international normalized ratio over several years with warfarin doses of 3.1–4.3 mg/day. This case report sheds further light on the clinical impact of CYP2C9 *11/*11 on warfarin dose requirements, short- and long-term treatment response and practical considerations for warfarin management in suspected carriers of rare variant CYP2C9 alleles.

Background The mortality rate is low in endocrine surgery, making it a difficult outcome to use for quality improvement in individual units. Lessons from population data sets are of value in improving outcomes. Data from the Australian and New Zealand Audit of Surgical Mortality (ANZASM) were used here to understand and elucidate potential systems issues that may contribute to preventable deaths. Methods ANZASM data relating to 30-day mortality after thyroidectomy, parathyroidectomy, and adrenalectomy from 2009 to 2020 were reviewed. Mortality rates were calculated using billing data. Thematic analysis of independent assessor reports was conducted to produce a coding framework. Results A total of 67 deaths were reported, with an estimated mortality rate of 0.03–0.07 per cent (38 for thyroidectomy (0.03–0.06 per cent), 16 for parathyroidectomy (0.03–0.06 per cent), 13 for adrenalectomy (0.15–0.33 per cent)). Twenty-seven deaths (40 per cent) were precipitated by clinically significant adverse events, and 18 (27 per cent) were judged to be preventable by independent ANZASM assessors. Recurrent themes included inadequate preoperative assessment, lack of anticipation of intraoperative pitfalls, and failure to recognize and effectively address postoperative complications. Several novel themes were reiterated, such as occult ischaemic heart disease associated with death after parathyroid surgery, unexpected intraoperative difficulties from adrenal metastasis, and complications due to anticoagulation therapy after thyroid surgery. Conclusion This study represents a large-scale national report of deaths after endocrine surgery and provides insights into these rare events. Although the overall mortality rate is low, 27 per cent of deaths involved systems issues that were preventable following independent peer review.

Primary aldosteronism is the most common surgically curable cause of endocrine hypertension. Management of the unilateral subtype of primary aldosteronism with adrenalectomy requires multidisciplinary input. It is unclear if a dedicated endocrine hypertension service confers better outcomes compared to standard care offered by individual clinicians.In this retrospective study, patients from the Monash University Endocrine Surgery Database were divided into either the endocrine hypertension service group, where patients were managed by a dedicated multidisciplinary team, or the standard group, where patients were managed by individual clinicians. The comparisons included patient selection for surgery, perioperative blood pressure control, and surgical cure rate.Despite similar perioperative blood pressure, patients in the endocrine hypertension service group (n = 41) were on fewer antihypertensive medications (1 vs 2, P = .011) compared to the standard group (n = 55). A larger proportion of patients in the endocrine hypertension service group had either bilateral adrenal nodules or no adrenal lesions on computed tomography (41% vs 18%, P = .013). Patients in the standard group had larger adrenal lesions on computed tomography (median 15 mm vs 10 mm, P = .032). Postoperatively, the biochemical cure rate was higher in the endocrine hypertension service group at 6 to 12 months (97% vs 76%, P = .021).Patients managed by endocrine hypertension service were more likely to be diagnosed with surgically curable primary aldosteronism without a unilateral adrenal adenoma on imaging, required fewer medications for perioperative blood pressure control, and experienced superior postoperative outcomes. Referral to a dedicated endocrine hypertension service is recommended for patients with primary aldosteronism who wish to pursue a surgical cure.

The abundance of docosahexaenoic acid (DHA) in brain membrane phospholipids has stimulated studies to explore its role in neurological functions. Upon released from phospholipids, DHA undergoes enzymatic reactions resulting in synthesis of bioactive docosanoids and prostanoids. However, these phospholipids are also prone to non-enzymatic reactions leading to more complex pattern of metabolites. A non-enzymatic oxidized product of DHA, 4(Rs)-4-F(4t)-Neuroprostane (44FNP), has been identified in cardiac and brain tissues. In this study, we examined effects of the 44FNP on oxidative and inflammatory responses in microglial cells treated with lipopolysaccharide (LPS). The 44FNP attenuated LPS-induced production of reactive oxygen species (ROS) in both primary and immortalized microglia (BV2). It also attenuated LPS-induced inflammation through suppressing NFκB-p65 and levels of iNOS and TNFα. In addition, 44FNP also suppressed LPS-induced mitochondrial dysfunction and upregulated the Nrf2/HO-1 antioxidative pathway. In sum, these findings with microglial cells demonstrated neuroprotective effects of this 44FNP and shed light into the potential of nutraceutical therapy for neurodegenerative diseases.

Background Studies have demonstrated increased risk of major atherothrombotic events in CYP2C19 loss‐of‐function (LOF) variant carriers versus non‐carriers treated with clopidogrel after percutaneous coronary intervention (PCI). We sought to evaluate real‐world outcomes with the clinical implementation of CYP2C19 ‐guided antiplatelet therapy after PCI. Methods and Results Data from 9 medical centers where genotyping was performed in the setting of PCI were included. Alternative therapy with prasugrel or ticagrelor was recommended for patients with a CYP2C19 LOF variant. The primary outcome was the composite of major atherothrombotic events (all‐cause death, myocardial infarction, ischemic stroke, stent thrombosis, or hospitalization for unstable angina) within 12 months following PCI. Moderate or severe/life‐threatening bleeding within 12 months was a secondary outcome. Among 3342 patients, 1032 (31%) were LOF carriers, of whom 571/1032 (55%) were treated with alternative therapy. In LOF carriers, the rate of major atherothrombotic events was lower in patients treated with alternative therapy versus clopidogrel (adjusted HR, 0.56; 95% CI 0.39–0.82). In those without a LOF allele, no difference was observed (adjusted HR, 1.07; 95% CI 0.71–1.60). There was no difference in bleeding with alternative therapy versus clopidogrel in either LOF carriers or those without a LOF allele. Conclusions Real‐world data demonstrate lower atherothrombotic risk in CYP2C19 LOF carriers treated with alternative therapy versus clopidogrel and similar risk in those without a LOF allele treated with clopidogrel or alternative therapy. These data suggest that PCI patients treated with clopidogrel should undergo genotyping so that CYP2C19 LOF carriers can be identified and treated with alternative therapy.

Summary Still’s disease, the paradigm of autoinflammation-cum-autoimmunity, predisposes for a cytokine storm with excessive T lymphocyte activation upon viral infection. Loss of function of the purine nucleoside enzyme FAMIN is the sole known cause for monogenic Still’s disease. Here we discovered that a FAMIN-enabled purine metabolon in dendritic cells (DCs) restrains CD4+ and CD8+ T cell priming. DCs with absent FAMIN activity prime for enhanced antigen-specific cytotoxicity, IFNγ secretion, and T cell expansion, resulting in excessive influenza A virus-specific responses. Enhanced priming is already manifest with hypomorphic FAMIN-I254V, for which ∼6% of mankind is homozygous. FAMIN controls membrane trafficking and restrains antigen presentation in an NADH/NAD+-dependent manner by balancing flux through adenine-guanine nucleotide interconversion cycles. FAMIN additionally converts hypoxanthine into inosine, which DCs release to dampen T cell activation. Compromised FAMIN consequently enhances immunosurveillance of syngeneic tumors. FAMIN is a biochemical checkpoint that protects against excessive antiviral T cell responses, autoimmunity, and autoinflammation., Graphical abstract, Highlights • A FAMIN-enabled purine metabolon in dendritic cells restrains T cell priming • FAMIN prevents cytoplasmic NADH/NAD+ reductive stress that enhances priming • Inosine generated from hypoxanthine by FAMIN inhibits T cell priming • FAMIN ameliorates immunopathology in influenza but dampens tumor surveillance, Saveljeva et al. identify a biochemical mechanism in dendritic cells that restrains T cell priming and prevents immunopathology but dampens tumor surveillance. FAMIN enables a purine nucleotide cycle, which prevents cytoplasmic NADH/NAD+ reductive stress that augments antigen presentation, and it generates inosine, which inhibits T cell activation.

Genotyping for CYP2C19 no function alleles to guide antiplatelet therapy after percutaneous coronary intervention (PCI) improves clinical outcomes. Although results for the increased function CYP2C19*17 allele are also reported, its clinical relevance in this setting remains unclear. A collaboration across nine sites examined antiplatelet therapy prescribing and clinical outcomes in 3,342 patients after implementation of CYP2C19-guided antiplatelet therapy. Risk of major atherothrombotic and bleeding events over 12 months after PCI were compared across cytochrome P450 2C19 isozyme (CYP2C19) metabolizer phenotype and antiplatelet therapy groups by proportional hazards regression. Clopidogrel was prescribed to a similar proportion of CYP2C19 normal (84.5%), rapid (82.9%), and ultrarapid metabolizers (80.6%) (P = 0.360). Clopidogrel-treated normal metabolizers (20.4 events/100 patient-years; adjusted hazard ratio (HR) 1.00, 95% confidence interval (CI), 0.75-1.33, P = 0.993) and clopidogrel-treated rapid or ultrarapid metabolizers (19.1 events/100 patient-years; adjusted HR 0.95, 95% CI, 0.69-1.30, P = 0.734) exhibited no difference in major atherothrombotic events compared with patients treated with prasugrel or ticagrelor (17.6 events/100 patient-years). In contrast, clopidogrel-treated intermediate and poor metabolizers exhibited significantly higher atherothrombotic event risk compared with prasugrel/ticagrelor-treated patients (adjusted HR 1.56, 95% CI, 1.12-2.16, P = 0.008). When comparing clopidogrel-treated rapid or ultrarapid metabolizers to normal metabolizers, no difference in atherothrombotic (adjusted HR 0.97, 95% CI, 0.73-1.29, P = 0.808) or bleeding events (adjusted HR 1.34, 95% CI, 0.83-2.17, P = 0.224) were observed. In a real-world setting of genotype-guided antiplatelet therapy, the CYP2C19*17 allele did not significantly impact post-PCI prescribing decisions or clinical outcomes. These results suggest the CYP2C19 *1/*17 and *17/*17 genotypes have limited clinical utility to guide antiplatelet therapy after PCI.

The high levels of docosahexaenoic acid (DHA) in cell membranes within the brain have led to a number of studies exploring its function. These studies have shown that DHA can reduce inflammatory responses in microglial cells. However, the method of action is poorly understood. Here, we report the effects of DHA on microglial cells stimulated with lipopolysaccharides (LPSs). Data were acquired using the parallel accumulation serial fragmentation method in a hybrid trapped ion mobility-quadrupole time-of-flight mass spectrometer. Over 2800 proteins are identified using label-free quantitative proteomics. Cells exposed to LPSs and/or DHA resulted in changes in cell morphology and expression of 49 proteins with differential abundance (greater than 1.5-fold change). The data provide details about pathways that are influenced in this system including the nuclear factor κ-light-chain-enhancer of the activated B cells (NF-κB) pathway. Western blots and enzyme-linked immunosorbent assay studies are used to help confirm the proteomic results. The MS data are available at ProteomeXchange.

In 2016, the International Society on Thrombosis and Haemostasis (ISTH) published guidelines advising caution when using direct oral anticoagulants (DOACs) in patients with morbid obesity due to limited clinical efficacy and safety data supporting their use in this patient population. In this review, we analyzed published articles in the MEDLINE database (from inception through May 29, 2019), and the Cochrane Library, Google Scholar, and EMBASE databases (from inception through April 26, 2019) that evaluated morbidly obese patients with atrial fibrillation (AF) or venous thromboembolism (VTE) who received DOACs. A total of 19 studies, which included pharmacokinetic studies, original phase III trials for the DOACs, post hoc analyses of phase III trials, and retrospective cohort studies, were evaluated. Although currently available data do not indicate that using DOACs in the morbidly obese is problematic, DOAC-specific pharmacokinetic variations have been observed. Additionally, less data evaluating DOAC efficacy and safety exist for VTE treatment compared with the data for stroke prevention in patients with AF. The overall quality of the studies included in this review was low due to limited prospective randomized trial data, limiting the ability to form definitive judgments on efficacy and safety DOACs in the morbidly obese. Continued caution is recommended when considering DOAC use in the morbidly obese, particularly for those requiring anticoagulation for VTE treatment, until additional higher-quality data become available.